The heart has a pumping mechanism consisting of periodic contraction and relaxation functions in the myocardium, which provides blood to the internal organs and tissues of the whole body through a process where the blood is constantly circulating and returning to the heart. This process is a constant, periodic action in which the myocardium is supplied the necessary oxygen and nutrition from coronary circulation of the right and left coronary arteries. In a normal functioning myocardium, the oxygen supply and consumption are maintained in the homeostatic state.
When the myocardium is unable to contract and relax properly resulting in damage to the pumping function, congestion in the general organs and tissues is induced and heart failure occurs. During heart failure, activation of the sympathetic nervous system occurs, as well as increased levels of norepinephrine in the blood, leading to an increase in heart rate.
Presently, there are drug treatments for heart failure such as β-blockers that decrease heart rate, and lessen the contractility force, resulting in a decrease of oxygen consumption required from the myocardium. However, at high doses, β-blockers increase the risk for heart failure and must be used or administered with caution.
The myocardium contracts and relaxes regularly and periodically. This cardiac cycle is divided into two phases; systolic phase and diastolic phase. The systolic phase is from the mitral valve closure to the aortic valve closure and the diastolic phase is from the aortic valve closure to the mitral valve closure. Moreover, diastolic phase has 4 stages; isovolumic relaxation, rapid left ventricular filling, slow left ventricular filling, and atrial contraction. In the latter 3 stages among the 4 stages; rapid left ventricular filling, slow left ventricular filling, and atrial contraction, the ventricular myocardium expands more and blood inflow from atrium to ventricle occurs. The diastolic function of the ventricle has important significance on the cardiac function. When myocardial expansion is impaired, the blood inflow to the ventricle is hindered and then heart failure, especially heart failure due to diastolic dysfunction, occurs. Moreover, blood flows from the coronary artery into the myocardial tissues during diastolic phase, which is different from that of other organs. The diastolic blood flow is remarkably more from the left coronary artery than the right coronary artery. Therefore, the diastolic impairment of left ventricle induces disturbance of coronary flow into the left ventricular myocardial tissues, generates myocardial ischemia, and as a result aggravates heart failure due to diastolic dysfunction.
Moreover, left ventricular diastolic impairment occurs in elderly people and in patients with hypertension and cardiac hypertrophy even without the presence of heart failure. Left ventricular diastolic impairments can easily be diagnosed using Doppler echocardiography. Some patients with left ventricular diastolic impairment complain of symptoms including fatigue, shortness of breath, chest discomfort and chest pain. During prolongation of left ventricular diastolic impairment, impairment of the cardiomyocytes and fibrosis in the myocardium eventually induce heart failure.
To maintain normal functions of the heart, the appropriate amounts of oxygen and nutrients required are supplied to the myocardium through coronary perfusion by the left and right coronary arteries. The contraction and relaxation of the myocardium requires the oxygen and nutrients to function properly.
The drugs used to dilate the coronary arteries leads to an increase of oxygen supply to the myocardium, thus reducing the risk of myocardial ischemia. Myocardial oxygen consumption is determined by the heart rate and cardiac contractility, and that drug decreases oxygen consumption by reducing heart rate and myocardial contractility, lowering the risk of myocardial ischemia. A drug capable of dilating the coronary artery combined with decreasing heart rate and contractility, is a treatment agent or a prophylactic agent for ischemic heart disease, such as angina pectoris and myocardial infarction.
Heart failure is divided into systolic failure and diastolic failure. In systolic failure, the left ventricular minimum diastolic pressure and left ventricular diastolic pressure both increase, therefore the drug reinforcing the left ventricular diastolic function is comprised of an agent that leads to the improvement of systolic failure.
Furthermore, a drug is a treatment agent for angina pectoris and myocardial infarction because it dilates the coronary artery and then enhances the oxygen supply to the myocardium. The consumption of oxygen from the myocardium is dependent upon the contractility force and heart rate. It is comprised of a drug that is a prophylactic agent for ischemic heart disease, such as angina pectoris and myocardial infarction. The β-blocker is a treatment agent for angina pectoris and myocardial infarction, however, it does not have the effect to dilate the coronary arteries or increase left ventricular diastolic function.
A drug, reinforcing the left ventricular diastolic function, decreasing heart rate, increasing reduction of contractility, combined with dilation of the coronary artery, is comprised of a treatment agent or a prophylactic agent for heart failure due to diastolic dysfunction.
Moreover, the relaxant function in the heart is equally important as systolic function and diastolic function. Relaxation is the main component in the first stage among the four stages of the diastolic phase; the function of isovolumic relaxation, which is able to be estimated using the maximal negative first derivative of the left ventricular pressure (−dP/dt) and the disturbance of relaxant function is able to be detected in the left ventricular wall motion by using Doppler echocardiography.
Heart failure is induced by numerous complexities such as myocardial systolic impairment, relaxation impairment, or diastolic impairment. Diastolic heart failure is generally formed with the complexities of diastolic impairment and relaxant impairment. Relaxant impairment is recognized in ischemic heart disease, atrial fibrillation, and ventricular arrhythmia and worsens severely, resulting in decreased cardiac contractility. The improvement of myocardial relaxant function is essential for the treatment of ischemic heart disease, atrial fibrillation, and ventricular arrhythmia. Relaxation impairment worsens severely and “Rigor” occurs, not allowing relaxation. Deterioration of relaxation impairment leads to heart failure.
Myocardial relaxation impairment is recognized in ischemic heart disease, hypertensive heart disease, heart failure, atrial fibrillation, and ventricular arrhythmia. There are still no drugs that allow a relaxant effect on the myocardium. Catecholamines such as epinephrine and norepinephrine (NE) stimulate to take the calcium uptake of the sarcoplasmic reticulum and promote myocardial relaxation. However, those substrates also increase heart rate and blood pressure, resulting in enhancement of myocardial oxygen consumption. It is difficult to use the treatment agents for the disease mentioned. The ideal drug is a myocardial relaxant which promotes myocardial relaxation without changing the heart rate. It is an agent that does not change heart rate and accelerates myocardial relaxation, and an agent which can improve ischemic heart disease, hypertensive heart disease, heart failure, atrial fibrillation, and ventricular arrhythmia, and cardiac function.
Blood pressure is determined by cardiac output, peripheral blood resistance, circulation blood volume, and blood viscosity. Norepinephrine increases the peripheral vascular resistance and raises blood pressure. It is a treatment agent or a prophylactic agent used to decrease blood pressure for hypertension due to norepinephrine-loaded hypertension.
Meanwhile, 4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-b enzothiazepine and derivatives thereof have been reported to have the effective compounds which inhibit myocardial necrosis including kinetic cell death (KD) and acute myocardial infarction without cardiac suppressive effects (Patent Documents 1 and 2). There have been many reports regarding its effectiveness on atrial fibrillation as well as its anticancer properties, for example, use for the treatment of atrial fibrillation (Patent Document 3), enhancement of anti-cancer agents for the treatment of cancer (Patent Document 4), use for the improvement or stabilization of the ryanodine receptor function, Ca2+ leak from the sarcoplasmic reticulum (Patent Document 5), muscle relaxation accelerator, treatment for left ventricular relaxation disturbance, treatment for angina pectoris, treatment for acute pulmonary emphysema, for improvement of microcirculation blood flow, for hypertension, for ventricular tachycardia and torsades de pointes (Patent Document 6).